Use of an H+, K+-ATPase inhibitor in the treatment of asthma

ABSTRACT

The invention provides a method for the treatment of polyposis which comprises treating a subject suffering from polyposis with an H + , K + -ATPase inhibitor and, optionally, a glucocorticoid. The invention also relates to a pharmaceutical formulation for simultaneous, separate or sequential administration in the treatment of Widal&#39;s Syndrome and in the treatment of asthma.

FIELD OF THE INVENTION

[0001] The present invention provides a new treatment for polyposisusing proton pump inhibitors (PPIs), i.e. H⁺, K⁺-ATPase inhibitors.

BACKGROUND OF THE INVENTION

[0002] Polyposis can generally arise in the nose and thegastrointestinal tract. In the nose, polyps are pale bags of tissue thatarise in the nasal cavity. Their paleness is generally due to poor bloodsupply. It is not known what causes the polyps to be formed but theirpresence is often associated with certain medical conditions, forexample asthma and aspirin intolerance. Within the general populationthe incidence of nasal polyps is low at around only 1% but 13% of asthmasufferers and 36% of aspirin intolerant asthmatics suffer from nasalpolyposis. The triple condition of nasal polyposis, aspirin intoleranceand asthma is known as Widal's Syndrome.

[0003] Nasal polyposis is generally treated in two stages. Initially areduction in size of the polyps is achieved either by surgery or by theapplication of a topical intranasal steroid preparation, for examplebetamethasone sodium phosphate. Once a reduction in size has beenobtained then long term maintenance of the reduction is necessary byregular use of an intranasal steroid spray such as beclomethasonedipropionate, budesonide, or fluticasone propionate. When rapidamelioration is required, oral steroids such as prednisolone ordexamethasone or synthetic adrenocorticotrophic hormones are used (see VJ Lund Diagnosis and treatment of nasal polyps Brit Med J 1995, 311,1411-4). There are also proposals that non-steroidal anti-inflammatorydrug can be used in the treatment of nasal polyposis (see WO 9703659-A).

DETAILED DESCRIPTION OF THE INVENTION

[0004] According to the invention there is provided a method for thetreatment of nasal polyps which method comprises treating a subjectsuffering from the said condition with an H⁺, K⁺-ATPase inhibitor. Theinvention further provides the use of an H⁺, K⁺-ATPase inhibitor in themanufacture of a medicament for the treatment of nasal polyps.

[0005] H⁺, K⁺-ATPase inhibitors are a known class of pharmaceuticalagents generally used in therapy for the treatment of gastric acidrelated diseases. Examples of H⁺, K⁺-ATPase inhibitors are for instancecompounds known under the generic names omeprazole, lansoprazole,pantoprazole, rabeprazole and leminoprazole. Some of these compounds arefor instance disclosed in EP-A1-0005129, EP-A1-174726, EP-A1-166287 andGB 2163747.

[0006] These pharmaceutical substances are generally known to be usefulfor inhibiting gastric acid secretion in mammals and man by controllinggastric acid secretion at the final step of the acid secretory pathway.Thus, in a more general sense, they may be used for prevention andtreatment of gastric-acid related diseases in mammals and man, includinge.g. reflux oesophagitis, gastritis, duodenitis, gastric ulcers andduodenal ulcers.

[0007] It has now surprisingly been found that H⁺, K⁺-ATPase inhibitorsare useful in the treatment of nasal polyps, particularly where knowntreatments have failed.

[0008] The H⁺, K⁺-ATPase inhibitors preferably used in the invention arecompounds of the general formula

[0009] wherein N in the benzimidazole moiety of Het₂ means that one ofthe ring carbon atoms substituted by R₆-R₉ optionally may be exchangedfor a nitrogen atom without any substituents;

[0010] R₁ and R₃ each independently represent hydrogen, alkyl, or alkoxyon the condition that R₁ and R₃ do not simultaneously represent alkoxy;and R₂ represents alkyl, alkoxy optionally substituted by fluorine,alkylthio or alkoxyalkoxy; or one of R₁ and R₃ is halogen and the otheris hydrogen and R₂ is 1-morpholino, 1-piperidino or dialkylamino;

[0011] R₄ and R₅ are the same or different and selected from hydrogenand alkyl;

[0012] R₆-R₉ are the same or different and selected from hydrogen,halogen, alkyl, alkoxy, haloalkoxy, alkylcarbonyl, and alkoxycarbonyl;

[0013] R₁₀ is hydrogen or R₁₀ and R₃ together complete a ring containing6 to 8 carbon atoms; and

[0014] R₁₁ represents hydrogen, halogen or alkyl;

[0015] wherein the compound of formula (I) is optionally in the form ofan pharmaceutically acceptable alkaline salt or in its neutral form oris a single enantiomer or a racemic mixture thereof;

[0016] wherein each alkyl or alkylenyl moiety has a branched or straightchain and has 1 to 6, preferably 1 to 4, carbon atoms;

[0017] wherein a halogen atom is preferably a fluorine, chlorine, orbromine atom, preferably a fluorine or chlorine atom.

[0018] Examples of particularly preferred compounds according to formulaI for use in the invention are

[0019] The H⁺, K⁺-ATPase inhibitor used in the invention is preferablyof formula (Ia): in other words it is preferably omeprazole, or analkaline salt of omeprazole, the (−)-enantiomer of omeprazole or analkaline salt thereof.

[0020] The compound of formula (I) when optionally in the form of apharmaceutically acceptable alkaline salt is preferably the Mg²⁺, Ca²⁺,Na⁺ or K⁺ salt, more preferably the Mg²⁺ salt.

[0021] The H^(+, K) ⁺-ATPase inhibitor used in the invention can beadministered orally, rectally or parenterally. While the effect of theinhibitors on the nasal polyps has been established in patients who havetaken omeprazole by the oral route, it is believed that the effect ofthe inhibitor on the polyps is a systemic effect that is not dependenton what mode of administration is used. Accordingly a reduction in sizeof the polyps should be obtainable with other routes of administration.

[0022] Commercially available pharmaceutical preparations of H⁺,K⁺-ATPase inhibitors are suitably used in the invention. Examples ofsuch preparations for omeprazole include enteric coated pellets ofomeprazole filled in capsules, or formulated into a multiple unit tableddosage form; enteric coated tablets of omeprazole or an alkaline saltthereof; and solutions for parenteral administration comprising analkaline salt of omeprazole.

[0023] The dose of the H⁺, K⁺-ATPase inhibitor to be administered willvary according to the type of nasal polyps to be treated and thecondition of the patient. However the dosage for oral, rectal or i.v.administration is generally in the range of from 1 to 100 mg of H⁺,K⁺-ATPase inhibitor per day. Normally an amount of from 10 to 40 mg perday is used for oral administration.

[0024] The invention may be applied in combination with other treatmentsknown to ameliorate the other symptoms generally associated with nasalpolyps, for example asthma. In other words, the invention can be appliedin the treatment of Widal's Syndrome which consists of the conditions ofnasal polyps, asthma and aspirin intolerance. The invention may also beapplied in the treatment of other inflammatory diseases in the upperrespiratory tract such as acute and chronic rhinosinusitis, allergic andnon-allergic rhinitis, as well as in the lower respiratory tract such asasthma. Therefore according to the invention there is further provided amethod for treating Widal's Syndrome and other respiratory tractinflammatory diseases which method comprises simultaneously, separatelyor sequentially administration to a subject suffering from the syndromeor the diseases a pharmaceutical formulation comprising an H⁺, K⁺-ATPaseinhibitor and a glucocorticoid. According to the invention there is alsoprovided a pharmaceutical formulation for simultaneous, separate orsequential administration to be used in the treatment of Widal'sSyndrome or in the treatment of asthma which formulation comprises anH⁺, K⁺-ATPase inhibitor and a glucocorticoid. The invention furtherprovides the use of an H⁺, K⁺-ATPase inhibitor and a glucocorticoid inthe manufacture of such a pharmaceutical formulation.

[0025] Preferred glucocorticoids are topically active anti-inflammatorysteroids. Examples of suitable steroids include budesonide; rofleponide;rofleponide palmitate; ciclesonide; momethasone furoate; fluticasonepropionate;16α,17α-butylidenedioxy-6α,9α-difluoro-11β,21-dihydroxypregna-1,4-diene-3,20-dione;6α,9α-difluoro-11β-hydroxy-16α,17α-dibutylidenedioxy-17α-methylthio-androsta-4-ene-3-one;S-methyl-16α,17α-butylidenedioxy-6α,9α-difluoro-11β-hydroxy-3-oxo-androsta-1,4-diene17β-carbothioate; methyl9α-chloro-6α-fluoro-11α-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17α-carboxylate;6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3S-yl) ester; tipredane; fluocinoloneacetonide; flunisolide; flumethasone; dexamethasone; betamethasone;beclomethasone dipropionate; deflazacort; cortivazol; or cortisol and/orhydrocortisol, optionally in their pure isomeric forms (where such formsexist) and in the forms of their pharmaceutically acceptable salts.

[0026] The steroids for use in the invention may be applied usingconventional dosing rates, e.g. 40 to 3000 μg per day. Administrationmay be by inhalation orally or intranasally. The steroids can optionallybe adapted to be administered from a dry powder inhaler, a pressurisedmetered dose inhaler, or a nebuliser.

[0027] When the steroids are administered from a pressurised inhaler,they are preferably in micronised form. They are suspended or dissolvedin a liquid propellant mixture. The propellants which can be usedinclude chlorofluorocarbons, hydrocarbons or hydrofluoroalkanes.Especially preferred propellants are P134a (tetrafluoroethane) and P227(heptafluoropropane) each of which may be used alone or in combination.They are optionally used in combination with other propellants and/orsurfactants and/or other excipients, for example ethanol, surfactants,lubricants, anti-oxidants and stabilising agents.

[0028] When the steroids are administered via a nebuliser they may be inthe form of a nebulised aqueous suspension or solution, with or withouta suitable pH or tonicity adjustment, either as a unit dose or multidosedevice.

[0029] The invention is described more in detail with reference to thefollowing examples.

EXAMPLE 1

[0030] A 53 year old woman who had had Widal's Syndrome for severalyears but who had refused surgical treatment of her polyps suffered mildupper abdominal pain and no improvement in the polyps after treatment bytopical and systemic corticosteroids. However within two weeks of beingprescribed 20 mg of omeprazole per day in addition to 100 μg ofbudesonide (Aqua preparation) per nostril/b.i.d. and 6 mg of deflazacortper day, she experienced a progressive improvement in her nasalrespiratory problem. Eventually she recovered completely from thepolyps.

EXAMPLES 2 TO 10

[0031] Nine patients, each with the conditions shown in the followingTable 1, were treated during a two week period. The treatment consistedof 20 mg of omeprazole, 100 μg of intranasal budesonide and 3 to 15 mgof oral deflazacort (deflazacort was used in such a small quantity toensure the patients' compliance). The results are also shown in Table 1.TABLE 1 Example No. Condition Result 2 Widal's Syndrome Temporarybenefit 3 Widal's Syndrome Positive effect 4 Widal's Syndrome Positiveeffect 5 Nasal Polyposis Long term benefit 6 Nasal Polyposis No benefit7 Nasal Polyposis Positive effect 8 Nasal Polyposis Positive effect 9Nasal Polyposis and aspirin Positive effect intolerance 10 NasalPolyposis and asthma No benefit

[0032] Where a positive effect is indicated, this means that the patientexperienced a decrease in rhinorrhoea, a marked improvement in nasalrespiratory ventilation and a reduction in the size of the polyps. Thepatient who experienced a temporary benefit by the treatment suffered arecurrence of the polyposis following the withdrawal of omeprazole anddeflazacort (topical anti-inflammatory steroids, i.e. budesonide, weretaken as required). However after treatment with the same regimen wasresumed, a marked reduction in the size of the polyps was achieved.

[0033] The patient of Example 5 who experienced a long term benefitinitially experienced no benefit at the end of the initial 2 weektreatment period but continued with omeprazole and was rewarded with apositive effect at the end of 2 months.

1. Use of an H⁺, K⁺-ATPase inhibitor in the manufacture of a medicamentfor the treatment of nasal polyps.
 2. Use of an H⁺, K⁺-ATPase inhibitorin the manufacture of a medicament for the treatment of Widal'sSyndrome.
 3. Use of an H⁺, K⁺-ATPase inhibitor and a glucocorticoid inthe manufacture of a pharmaceutical formulation intended forsimultaneous, separate or sequential administration in the treatment ofWidal's Syndrome.
 4. Use of an H⁺, K⁺-ATPase inhibitor and aglucocorticoid in the manufacture of a pharmaceutical formulationintended for simultaneous, separate or sequential administration in thetreatment of asthma.
 5. Use according to claim 3 wherein theglucocorticoid is a topically active anti-inflammatory steroid.
 6. Useaccording to claim 4 wherein the glucocorticoid is budesonide,beclomethasone dipropionate or fluticasone propionate.
 7. Use accordingto any one of the preceding claims wherein the H⁺, K⁺-ATPase inhibitoris a compound of formula

wherein N in the benzimidazole moiety of Het₂ means that one of the ringcarbon atoms substituted by R₆-R₉ optionally may be exchanged for anitrogen atom without any substituents; R₁ and R₃ each independentlyrepresent hydrogen, alkyl, or alkoxy on the condition that R₁ and R₃ donot simultaneously represent alkoxy; and R₂ represents alkyl, alkoxyoptionally substituted by fluorine, alkylthio or alkoxyalkoxy; or one ofR₁ and R₃ is halogen and the other is hydrogen and R₂ is 1-morpholino,1-piperidino or dialkylamino; R₄ and R₅ are the same or different andselected from hydrogen and alkyl; R₆-R₉ are the same or different andselected from hydrogen, halogen, alkyl, alkoxy, haloalkoxy,alkylcarbonyl, and alkoxycarbonyl; R₁₀ is hydrogen or R₁₀ and R₃together complete a ring containing 6 to 8 carbon atoms; and R₁₁represents hydrogen, halogen or alkyl; wherein the compound of formula(I) is optionally in the form of a pharmaceutically acceptable alkalinesalt or in its neutral form or is a single enantiomer or a racemicmixture thereof; wherein each alkyl or alkylenyl moiety has a branchedor straight chain and has 1 to 6 carbon atoms.
 8. Use according to claim7 wherein the compound of formula (I) is a compound of formula

or an alkaline salt thereof, or the (−)-enantiomer or an alkaline saltof the (−)-enantiomer.
 9. A method for the treatment of nasal polypswhich method comprises treating a subject suffering from the saidcondition with a pharmaceutical formulation comprising an H⁺, K⁺-ATPaseinhibitor.
 10. A method for the treatment of Widal's Syndrome whichcomprises treating a subject suffering from the syndrome with apharmaceutical formulation comprising an H⁺, K⁺-ATPase inhibitor.
 11. Amethod for the treatment of Widal's Syndrome which comprisessimultaneously, separately or sequentially administration to a subjectsuffering from the syndrome with a pharmaceutical formulation comprisingan H⁺, K⁺-ATPase inhibitor and a glucocorticoid.
 12. A method for thetreatment of asthma which comprises simultaneously, separately orsequentially administration to a subject suffering from the syndromewith a pharmaceutical formulation comprising an H⁺, K⁺-ATPase inhibitorand a glucocorticoid.
 13. A method according to claim 11 wherein theglucocorticoid is a glucocorticoid defined in claim 5 or
 6. 14. A methodaccording to any one of claims 9 to 13 wherein the H⁺, K⁺-ATPaseinhibitor is a compound of the formula defined in claim 7 or
 8. 15. Apharmaceutical formulation for simultaneous, separate or sequential usein the treatment of Widal's Syndrome which formulation comprises an H⁺,K⁺-ATPase inhibitor and a glucocorticoid.
 16. A pharmaceuticalformulation for simultaneous, separate or sequential administration inthe treatment of asthma which pharmaceutical formulation comprises anH⁺, K⁺-ATPase inhibitor and a glucocorticoid.
 17. A pharmaceuticalformulation according to claim 15 or 16 wherein the glucocorticoid is aglucocorticoid defined in claim 5 or
 6. 18. A pharmaceutical formulationaccording to any of claims 15-17 wherein the H⁺, K⁺-ATPase inhibitor isa compound of the formula defined in claim 7 or 8.